Crohn's disease (CD) is a debilitating chronic condition with no known cure. Although there is evidence for the involvement of genetic, immunological, and environmental mechanisms, the precise cause(s) of CD remain unclear. Indirect evidence suggest that CD may be initiated by a dysregulated innate immune response against an "unknown" antigen in a genetically susceptible host. The major strengths of this competitive renewal are the unique SAMP1/YitFc (SAMP) mouse model, which has been extensively characterized by our group during the last funding period, and the highly synergistic nature of the program. The overall objective of this continuation proposal is to investigate the key pathogenic mechanisms underlying this spontaneous murine model of CD. The Program Project will continue to be directed by Dr. Fabio Cominell, and will consist of 5 projects and 2 cores. Project 1, headed by Dr. Cominelli, will extend its focus on the role of pivotal cytokines in mediating chronic intestinal inflammation in this model. Project 2, headed by Dr. Marcia McDuffie, will identify susceptibility genes involved in the predisposition to ileitis in SAMP mice based on the chromosomal loci identified during the previous funding period. Project 3, headed by Dr. Steven Cohn, will investigate the role of Paneth cells and their defensins in initiating ileitis. Project 4, headed by Dr. Klaus Ley, will study the mechanisms of lymphocyte homing and trafficking in SAMP mice, with a particular focus on L-selectin and PSGL-1. Project 5, a new project headed by Dr. Theresa Pizarro, will investigate the role of epithelial innate immune responses in initiating and perpetuating ileitis in SAMP mice. This Program is supported by an Administrative Core, which coordinates the program, and an Animal Core, which centralizes the production and breeding of SAMP mice and other congenic lines. The long-term goal of this Program Project is to understand the key pathogenic mechanisms of experimental CD, to aid development of a cure for at least a subgroup of patients with this devastating disease.